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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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LL 3858, SUDOTERB


SUDOTERB.png

Figure imgf000023_0002

LL 3858, SUDOTERB

UNII-SK2537665A;

CAS 676266-31-2;

N-[2-methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]pyrrol-1-yl]pyridine-4-carboxamide;

N-[2-Methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]methyl]-1H-pyrrol-1-yl]-4-pyridinecarboxamide

Sudoterb(TM)

Molecular Formula: C29H28F3N5O
Molecular Weight: 519.572 g/mol
  • Originator Lupin
  • Class Antituberculars; Isonicotinic acids; Pyrroles
  • Mechanism of Action Undefined mechanism
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • No development reported Tuberculosis

Most Recent Events

  • 23 Jul 2015 No recent reports on development identified – Phase-II for Tuberculosis in India (unspecified route)
  • 11 Dec 2013 Lupin completes a phase II trial in Tuberculosis in India prior to December 2013 (CTRI2009-091-000741)
  • 31 Jul 2010 Lupin completes enrolment in its phase II trial for Tuberculosis in India (CTRI2009-091-000741)

img

Sudoterb HCl
CAS: 1044503-04-9 (2HCl)
Chemical Formula: C29H30Cl2F3N5O
Molecular Weight: 592.4882

Image result

Image result for sudoterb

SYNTHESIS

WO 2006109323

Tuberculosis (TB) is a contagious disease, which usually runs a protracted course, ending in death in majority of the cases, with relapse being a common feature of the disease. It is one of the most important causes of prolonged disability and chronic ill health. It is caused by the tubercle bacillus Mycobacterium tuberculosis, which is comparatively difficult to control. Drugs such as isoniazid, rifampicin, pyrazinamide, ethambutol streptomycin, para- aminosalisylic acid, ethionamide, cycloserine, capreomycin, kanamycin, thioacetazone etc. have been and are being currently used to treat TB. Amongst these, isoniazid, rifampicin, ethambutol and pyrazinamide are the first-line drugs of choice, which are administrated either as a single drug formulation or as a fixed-dose combination of two or more of the aforesaid drugs. Even though, each of the abovementioned first-line drug regimen is highly effective for treatment of TB, however, they are associated with shortcomings, such as unpleasant side- effects and relatively long course of treatment. The later one results in non-compliance of the patient to the treatment leading often to failure of the treatment and most importantly, development of drug resistance. The development of drug resistance has long constituted a principal difficulty in treating human tuberculosis. The second-line drugs, on the other hand are less effective, more expensive and more toxic.

It is estimated that in the next twenty years over one billion people would be newly infected with TB, with 35 million people succumbing to the disease (WHO Fact Sheet No. 104, Global

Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB

Development : http://www.who.int/inf-fs/en/factl04.hfaiil). With the emergence of HIV related

TB, the disease is assuming alarming proportions as one of the killer diseases in the world today.

A major thrust in research on antimycobacterials in the last decade has witnessed the development of new compounds for treatment of the disease, a) differing widely in structures, b) having different mode/mechanism of action, c) possessing favourable pharmacokinetic properties, d) which are safe and having low incidence of side-effects, and e) which provide a cost-effective dosage regimen.

Several new class of compounds have been synthesized and tested for activity against Mycobacterium tuberculosis, the details of chemistry and biology of which could be found in a recent review by B. N. Roy et. al. in J. Ind. Chem. Soc, April 2002, 79, 320-335 and the references cited therein.

Substituted pyrrole derivatives constitute another class of compounds, which hold promise as antimycobacterial agents. The pyrrole derivatives which have been synthesized and tested for antitubercular as well as non-tubercular activity has been disclosed by : a) D. Deidda et. al. in Antimicrob. Agents and Chemother., Nov 1998, 3035-3037. This article describes the inhibitory activity shown by one pyrrole compound, viz. BM 212 having the structure shown below, against both Mycobacterium tuberculosis including drug-resistant mycobacteria and some non-tuberculosis mycobacteria.

Figure imgf000004_0001

The MIC value (μg/ml) against the M. tuberculosis strain 103471 exhibited by BM 212 was 0.70 as against 0.25 found for isoniazid.

b) M. Biava et. al. in J. Med. Chem. Res., 1999, 19-34 have reported the synthesis of several analogues of BM 212, having the general formula (The compounds disclosed by M. Biava et. al. inJ. Med. Chem. Res., 1999, 19-34.) shown hereunder

Figure imgf000005_0001

wherein,

Figure imgf000005_0002

X is H, . CH2— (Oy-Cl ; CH2-(CH2)4-CH3

Figure imgf000005_0003
Figure imgf000005_0004

Z is H ; Y

and the in vitro antimicrobial activity of the compounds against Candida albicans, Candida sp, Cryptococcus neoforma s, Gram- positive or Gram-negative bacteria, isolates of pathogenic plant fungi, Herpes simplex virus, both HSV1 and HSN2, M. tuberculosis, M. smegmαtis, M. mαrinum and M. αvium.

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 4-16.

M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988. This article describes the synthesis of pyrrole compounds of formula (: The compounds disclosed by M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988) shown hereunder

Figure imgf000006_0001

wherein,

X is H or Cl Y is H or Cl

R is N-methyl piperazinyl or thiomorphinyl

and their respective in vitro activity against M. tuberculosis and non-tuberculosis species of mycobacteria .

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 2-4.

d) F. Cerreto et. al. in Eur. J. Med. Chem., 1992, 27, 701-708 have reported the synthesis of certain 3-amino-l,5-diary-2 -methyl pyrrole derivatives and their in vitro anti-fungal activity against Candida albicans and Candida sp. However, there is no report on the activity of such compounds against M. tuberculosis.

e) C. Gillet et. al. in Eur. J. Med. Chem.-Chimica Therapeutica, March- April 1976, ϋ(2), 173-181 report the synthesis of several pyrrole derivatives useful as anti-inflammatory agents and as anti-allergants.

f) R. Ragno et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432. This article reports the synthesis and biological activity of several pyrrole derivatives as well as describes a structure activity relationship between the said pyrrole compounds and antimycobacterial activity. The compounds (The compounds disclosed by R. Rango et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432)synthesized and tested by the authors is summarized hereunder

Figure imgf000007_0001

wherein,

X is COOH, COOEt, CONHNH2, CH2OH, CH(OH)C6H5, NO2

Figure imgf000007_0002

Y is H, CH3, OCH3, CH2, SO2, or a group of formula

Figure imgf000007_0003

wherein,

R is H, Cl, C2H5, or OCH3 and R1 is H, Cl, F, CH3, or NO2,

A is H or R

Z is a group of formula,

Figure imgf000007_0004

R2 is H, Cl, OH, or OCH3 and R3 is H or Cl

None of the abovementioned disclosures report or suggest the in vivo efficacy including toxicity of any of the compounds described therein against experimental tuberculosis in animal model. Moreover, the higher MIC values of the compounds reported suggest that they may not be very effective in inhibition of Mycobacterium tuberculosis.

NO PIC

Sudershan Kumar Arora

sudershan arora, Formerly: President R&D, Ranbaxy Lab Limited,

Experience

Inventors Sudershan Kumar AroraNeelima SinhaSanjay JainRam Shankar UpadhayayaGourhari JanaShankar AjayRakesh Kumar Sinha
Applicant Lupin Limited

PATENT

WO 2004026828

https://www.google.com/patents/WO2004026828A1?cl=en

PATENT

US 20050256128

PATENT

https://encrypted.google.com/patents/WO2005107809A2?cl=en

Thus the invention relates to an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methy 1-5 -phenyl- pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non- toxic salt thereof

Figure imgf000011_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected from the group consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Further according to the invention there is provided a process for preparation of an antimycobacterial pharmaceutical composition comprising combining a compound of formula I or a pharmaceutically acceptable salt thereof

Figure imgf000011_0002

and one or more of the first line antitubercular drugs using a dry granulation method, a wet granulation method or a direct compression method. The present invention further provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) the compound of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected firom isoniazid, rifampicin, ethambutol and pyrazinamide for treatment of multi-drug resistant tuberculosis including latent tuberculosis. The present invention provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0002

and a therapeutically effective amount of one or more first line antitubercular drugs selected from isoniazid, rifampicin, ethambutol and pyrazinamide for treatment and/or inhibition of one or more mycobacterial conditions/ cells including but not limited to sensitive and multi- drug resistant strains of Mycobacterium tuberculosis, Mycobacterium avium – intracellular complex, M. fortutium, M. kansasaii and other related mycobacterial species.

ynthesis of Compound of Formula (I) The compound of formula (I) and the pharmaceutically acceptable salts thereof can be synthesized by any known method including but not limited to the methods disclosed in our PCT Application No. PCT/IN02/00189 (WO 04/026828 Al), which is incorporated herein by reference. An example of the preparation of N-(3-[[4-(3-trifluoromethylphenyl) piperazinyl]methyl]-2-methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide is as follows:

Preparation of N-(3 ~[[4-(3 -trifluoromethylphenyl)piperazinyl]methyl)] -2-methyl-5 – phenylpyrrolyl)-4-pyridylcarboxamide

Step l 1 -(4-chlorophenyl)pentane- 1 ,4-dione To a well stirred suspension of anhydrous aluminium chloride (27.0gm, 205.9mmol) in

126ml. of chlorobenzene was added oxopentanoylchloride (23.0gm, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30EC). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2 x 100ml.), brine (100 ml.) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6gm (24.07%) of the title compound.

Step 2 N-(5-methyl-2-phenylpyrrolyl)-4 pyridylcarboxamide

A mixture of 1- (chlorophenyl)pentane-l,4-dione (6.0g, 28.50 mmol, as obtained in Step-1) and isonicotinic hydrazide (4.30gm, 31.35 mmol) in benzene (6.0 ml.) was refluxed by over molecular sieves. After two hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2 x 100 ml.) and brine (1 x 50 ml.). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained as purified by column chromatography over silica gel (100-200 mesh) using 0.2% methanol in chloroform as eluent to give 3.50gm (39.42%) of the title compound.

Step 3 N-(3 – { [4-(3-trifuoromethylphenyl)piperazinyl]methyl} -2-methyl-5 -phenylpyrrolyl)-4- pyridylcarboxamide

To a stirred solution of N-(5-methyl-2-phenylpyrrolyl)-4-pyridylcarboxamide (0.300gm, 1.083 mmol, as obtained in Step-2) in acetonitrile (5.0 ml.) was added a mixture of l-(3-trifluoromethylphenyl)piperazine hydrochloride (0.288gm, 1.083mmol), 40% formaldehyde (0.032gm, 1.083 mmol) and acetic acid (0.09 ml), drop-wise. After the completion of addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with sodium hydroxide (20% aq. Soln.) and extracted with ethyl acetate (2 x 50 ml.). The combined ethyl acetate extract was washed with water (2 x 25 ml.), brine (1-χ 20 ml.), and dried over anhydrous sodium sulfate and the solvent evaporated off. TLC of the crude product indicated two spots, which were separated by column chromatography over silica gel (100-200mesh). The more polar compound a eluted out using 80% ethyl acetate- hexane mixture was obtained in 24.34 % (0.130 gm) and was identified as N-(3-{[4-(3- trifluoromethylphenyl)piperazinyl]methyl}-2-methyl-5-phenylpyrrolyl)-4- pyridylcarboxamide m.p.80-82°C, MS: m/z 520 (M+l)

1HNMR(CDC13, *): 2:13 (s, 3H,CH3), 2.60 (bs, 4H, 2xN-CH2), 3.18 (bs, 4H, 2xN-CH2), 3.41 (s, 2H, N-CH2), 6.24 (s, lH,H-4), 6.97-7.03 (4H, m, ArH), 7.22-7.29 (m, 5H,AιΗ), 7.53 (d, 2H, J=6Hz, pyridyl ring), 8.50 (bs, 1H,NH D2O exchangeable), 8.70 (d, 2H, J=6Hz, pyridyl ring).

PATENT

WO 2006109323

Compounds of Formula I are known from PCT International Patent Application WO 2004026828, and were screened for antimycobacterial activity, in various in vitro and in vivo models in mice and guinea pigs. Several compounds exhibited strong antimycobacterial activity against sensitive and MDR strains of Mycobacterium tuberculosis in the in vitro and in vivo experiments. Further the compounds of Formula I were also found to be bioavailable, less toxic and safe compared to available anti TB drugs in various animal models.

Thus compounds of Formula I are useful for the effective treatment of Mycobacterium tuberculosis infection caused by sensitive/MDR strains. PCT International Patent Application WO 2004026828 also discloses the synthesis of compounds of Formula I,

Figure imgf000004_0001

wherein,

Ri is phenyl or substituted phenyl

R2 is selected from a group consisting of i) phenyl which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F, or, ii) pyridine, or iii) naphthalene, or iv) NHCOR4 wherein R4 is aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl. R3 is selected from a group of formula

/~-\ /-Un

— N N-R5 and — N X

wherein R5 is phenyl which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, Ci-C4 alkyl, Ci-C4 alkoxy, nitro, amino, haloalkyl, haloalkoxy etc.; unsubstituted or substituted benzyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroaroyl; unsubstituted or substituted diphenylmethyl,

n = 0-2 and X = -NCH3, CH2, S, SO, or SO2

Such that when R2 is phenyl, which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F; R5 is not Ci-C4 alkyl, or X is not -NCH3, CH2, S, SO, or SO2, when n = 1, or X is not -CH2 when n = 0 which comprises reacting the compound of Formula Il

»o-i >-CH, (H)

O O

with thionyl chloride, followed by reaction with RiH (wherein Ri is phenyl or substituted phenyl) in presence of aluminium chloride, and then condensation with R2NH2 (wherein R2 is as described above) in presence of p-toluenesulphonic acid to yield the corresponding unsubstituted pyrrole derivatives of Formula V,

Figure imgf000005_0001

which on further treatment with suitable secondary amines in the presence of formaldehyde and acetic acid afforded the desired pyrrole derivatives of Formula I,

Figure imgf000006_0001

which, on reacting with hydrochloric acid give a hydrochloride salt of compound of Formula Ia. wherein m = 1-2, Ri, R2 and R3 are the same as defined earlier. The above-mentioned methods in the prior art for the synthesis of compound of the Formula I suffer from the limitations,

1. In methods described in PCT International Patent Application WO 2004026828 for the synthesis of compounds of Formula I, positional isomers, the compound of Formula I’, are formed. The necessity of their removal through column chromatography decreases the yield of final pure product.

Figure imgf000006_0002

2. The synthesis of oxopentanoyl chloride (compound of Formula III) for the synthesis of compound of Formula I has been described in J. Org. Chem.

1960, 25, 390-392. It comprises reaction of levulinic acid with thionyl chloride at 50 0C for 1h, which results in poor yield.

3. In method described in PCT International Patent Application WO 2004026828 for the synthesis of 1-aryl-pentane-1,4-dione (compound of Formula IV), impurities are formed and purification involves column chromatography which decreases the yield of the product. 4. The synthesis of the intermediate of Formula V requires the use of benzene and high temperature conditions, which involves the formation of undesired by- products.

5. The above-mentioned methods in prior art for the synthesis of all the intermediates and final compounds of Formula I involves column chromatography for purification, which is cumbersome, tedious and not practicable on an industrial scale.

Example 1: Preparation of /V-(2-methyl-5-phenyl-3-f4-C3-trifluoromethyl-phenyl)- piperazin-1-ylmethyli-pyrrol-i-ylHsonicotinamide hydrochloride

Step (a): Preparation of 4-oxo-pentanoyl chloride

To a stirred mixture of levulinic acid (340.23 g, 2.93 mol) and Λ/./V- dimethylformamide (6.8 mL, catalytic amount) was added thionyl chloride (367.36 g, 3.087 mol, 1.05 equivalent) drop-wise at 20-30 0C in 1.5-2.0 h. After the complete addition of thionyl chloride, the reaction mixture was stirred at same temperature for 0.5 h (completion of reaction or formation of acid chloride was monitored by GC). After the completion of reaction, thionyl chloride was distilled off under reduced pressure at 20-30 0C. Traces of thionyl chloride were removed by adding benzene (136 mL) under reduced pressure at 30-35 0C and residue was dried at reduced pressure (1-2 mm) at 20-30 0C for 30-60 min to yield 370 g (93.8%) of 4-oxo-pentanoyl chloride as light orange oil. Step (b): Preparation of 1-phenyl-pentane-1,4-dione

Figure imgf000016_0001

(B) (A)

To a stirred suspension of benzene (3700 mL, 10 T w/v of acid chloride) and anhydrous aluminium chloride (440.02 g, 3.30 mol, 1.20 equivalent) was added A- oxo-pentanoyl chloride (370 g, 2.75 mol) drop-wise; the rate of addition was regulated so that the addition required 1.5-2 h and the temperature of the reaction mixture was kept at 25-35 0C. The reaction was completed in 2 h and monitored by GC. After completion of reaction, the reaction mixture was added slowly into cold (5-10 0C) 5% HCI (3700 mL) solution maintaining the temperature below 30 0C. The layers were separated; aqueous layer was extracted with ethyl acetate (1×1850 mL). The combined organic phase was washed with water (1 *1850 mL), 5% NaHCO3 solution (1×1850 mL), water (1×1850 mL), 5% NaCI solution (1×1850 mL), dried (Na2SO4), filtered and concentrated under reduced pressure at 35-40 0C, which was finally dried under reduced pressure (1-2 mm) at 35-400C to yield 185.6 g (38.3%) of 1-phenyl-pentane-1,4-dione as thick oil.

Step (c): Preparation of /V-(2-methyl-5-phenyl-pyrrol-1-yI)-isonicotinamide

A mixture of 1-(phenyl)-pentane-1,4-dione (185 g, 1.05 mol), isonicotinic hydrazide (158.4 g, 1.155 mol, 1.1 equivalent), p-toluenesulphonic acid (1.85 g, 1% w/w) and dichloromethane (1850 ml_) was heated under reflux at 40-50 0C under azeotropic distillation for 2-3 h (water was collected in dean stark apparatus). The completion of reaction was monitored by HPLC. After cooling to 25-30 0C the resulting mixture was washed with saturated NaHCO3 solution (1×925 mL), aqueous layer was back extracted with EtOAc (1×925 ml_). The combined organic layers were washed with water (1×925 mL), 5% brine solution (1×925 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to obtain the solid product, which was further dried under reduced pressure (1-2 mm) at 35-40 0C. To this, cyclohexane (925 mL) was added and stirred for 25-30 min, solid separated out was filtered washed with cyclohexane (370 mL). This process was repeated two times more with the same amount of cyclohexane and finally solid was dried under reduced pressure (1-2 mm) at 40-500C; yield 162.23 g (55.7%). White solid, mp 177-179 0C. 1H NMR (CDCI3): δ 2.10 (s, 3H), 5.98 (d, J = 3.4 Hz, 1H), 6.22 (d, J = 3.7 Hz, 1H), 7.237.28 (m, 5H), 7.50 (d, J = 5.6 Hz, 2H), 8.55 (d, J = 5.0 Hz, 2H), 9.82 (s, 1H). MS: m/z (%) 278 (100) [M+1]. Anal. Calcd for C17H15N3O (277.32): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.92; H, 5.67; N, 15.29.

Step (d): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide

To a stirred solution of Λ/-(2-methyl-5-phenyl-pyrrol-1-yl)-isonicotinamide (160 g, 0.577 mol) in acetonitrile (1600 mil), was added drop-wise through pressure equalizing funnel a mixture of 1-(3-trifluoromethyl-phenyl)-piperazine monohydrochloride (153.75 g, 0.667 mol, 1.155 equivalent), formaldehyde (17.34 g, 0.577 mol, 1.0 equivalent) and acetic acid (480 mL) at 25-30 0C over a period of 60-90 min. The resulting reaction mixture was stirred for 14-16 h at same temperature and completion of reaction was monitored by TLC. After the completion of reaction, reaction mixture was treated with 20% aqueous NaOH solution (2600 mL). Layers were separated, EtOAc (4000 mL) was added to organic layer, washed with water (2×2000 mL), brine (2×1250 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure at 35-38 0C and then dried under reduced pressure (1-2 mm) to yield the mixture of Λ/-{5-methyl-2-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol- 1-yl}-isonicotinamide (A) and Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (B), yield 289 g (97.8%). The ratio of A and B was determined by reverse phase HPLC, which was found to be 19.4% and 76.7%, respectively.

Step (e): Purification of yV-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide i) The mixture of A and B obtained from Step (d) (279 g) was dissolved in EtOAc (1960 ml_, 7 times) by heating at 50-60 0C. To this activated charcoal (14 g) was added and stirred for 10 min at the same temperature, filtered the activated charcoal through celite bed at 50-60 0C, washed with EtOAc (560 mL). After cooled to 25-30 0C, cyclohexane (2800 mL) was added to the filtrate and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was filtered, washed with cyclohexane (3500 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 151 g (52%). Ratio of A and B was found to be 1.7% and 96.6%, respectively.

ii) The mixture of A and B obtained from Step (e)(i) (151 g) was dissolved in

EtOAc (755 mL, 5 times) by heating at 50-60 0C. After cooled to 25-30 0C, cyclohexane (1510 mL) was added and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was frltered, washed with cyclohexane (3000 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 140 g (92%). Ratio ofA and B was found to be 0.2% and 98.1%, respectively.

Off white solid, mp 191-193 0C. 1H NMR (CDCI3): δ 2.13 (s, 3H), 2.60 (br s, 4H), 3.13 (br s, 4H), 3.41 (s, 2H), 6.24 (s, 1H), 6.977.29 (m, 9H), 7.53 (d, J = 5.6 Hz, 2H), 8.50 (S, 1H), 8.70 (d, J = 5.6 Hz, 2H). 13C NMR (CDCI3): δ 165.93, 151.77, 150.86, 139.74, 133.02, 131.99, 131.43, 129.92, 129.01, 127.79, 127.49, 121.74, 119.09, 116.18, 115.05, 112.48, 109.51, 54.87, 52.99, 48.93, 9.77. MS: m/z (%) 520 (100) [M+U Anal. Calcd for C29H28F3N5O (519.56): C, 67.04; H, 5.43; N, 13.48. Found: C, 67.36; H, 5.71; N, 13.69.

The free base Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1- ylmethyl]-pyrrol-1-yl}-isonicotinamide is obtained in a crystalline form having characteristic powder X-ray diffraction pattern given in Figure 1 with 2Θ values 4.85, 5.99, 6.83, 7.34, 9.15, 9.78, 10.93, 11.98, 13.17, 13.98, 14.33, 14.75, 15.73, 16.42, 17.11. 17.72, 17.95, 18.32, 19.11, 19.75, 20.32, 21.36, 22.04, 23.19, 25.17

Step (f): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide hydrochloride

To a stirred solution of 6% w/v HCI-EtOAc solution (821.8 mL, 1.351 mol, 7.0 equivalent) in EtOAc (2000 mL) was added a solution of Λ/-{2-methyl-5-phenyl-3- [4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (100 g, 0.193 mol) in EtOAc (2000 mL) through dropping funnel at 15-20 0C. When the addition was completed (~60 min), the reaction mixture was stirred at 10-150C for 1 h and then nitrogen gas was passed through reaction mass for 1 h until all the excess HCI fumes were removed. Solid so obtained was filtered through suction in an inert atmosphere, washed with ethyl acetate (2×500 mL), diisopropyl ether (2×500 mL) and dried in vacuum oven under reduced pressure (1-2 mm) at 35-40 0C for 15-20 h. Yield 115 g (99%).

Yellow solid, mp 177-179 0C. 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.11-3.42 (m, 6H), 3.93-4.23 (m, 4H), 6.62 (s, 1H), 7.09-7.51 (m, 9H), 8.19-8.21 (d, 2H, J = 4.6 Hz), 8.95-8.97 (d, 2H1 J = 4.6 Hz), 11.30 (br s, 1H), 12.86 (s, 1H). MS: m/z (%) 520 (100) [M+1]. Anal. Calcd for C29H28F3N5O.2HCI.3H2O (646.53): C, 53.87; H, 5.61; N, 10.83. Found: C, 53.67; H, 5.59; N, 10.86.

The product obtained was amorphous in nature having the characteristic X-ray powder diffraction pattern given in Figure 2.

Cited Patent Filing date Publication date Applicant Title
WO2004026828A1 * Sep 20, 2002 Apr 1, 2004 Lupin Limited Pyrrole derivatives as antimycobacterial compounds
WO2005107809A2 * Aug 27, 2004 Nov 17, 2005 Lupin Limited Antimycobacterial pharmaceutical composition comprising an antitubercular drug
US3168532 * Jun 12, 1963 Feb 2, 1965 Parke Davis & Co 1, 5-diarylpyrrole-2-propionic acid compounds
Reference
1 * BIAVA M ET AL: “SYNTHESIS AND MICROBIOLOGICAL ACTIVITIES OF PYRROLE ANALOGS OF BM 212, A POTENT ANTITUBERCULAR AGENT” MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 9, no. 1, 1999, pages 19-34, XP008016949 ISSN: 1054-2523
2 * BIAVA, MARIANGELA ET AL: “Antimycobacterial compounds. New pyrrole derivatives of BM212” BIOORGANIC & MEDICINAL CHEMISTRY , 12(6), 1453-1458 CODEN: BMECEP; ISSN: 0968-0896, 2004, XP002390961
3 * PARLOW J.J.: “synthesis of tetrahydonaphthaenes. part II” TETRAHEDRON, vol. 50, no. 11, 1994, pages 3297-3314, XP002391102
4 * R. RIPS , CH. DERAPPE AND N. BII-HOÏ: “1,2,5-trisubstituted pyrroles of pharmacologic interest” JOURNAL OF ORGANIC CHEMISTRY, vol. 25, 1960, pages 390-392, XP002390960 cited in the application

REFERENCES

1: Didilescu C, Craiova UM. [Present and future in the use of anti-tubercular
drugs]. Pneumologia. 2011 Oct-Dec;60(4):198-201. Romanian. PubMed PMID: 22420168.

2: Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects
in chemotherapy of tuberculosis. Respirology. 2010 Jul;15(5):764-78. doi:
10.1111/j.1440-1843.2010.01775.x. Review. PubMed PMID: 20546189; PubMed Central
PMCID: PMC4461445.

3: LL-3858. Tuberculosis (Edinb). 2008 Mar;88(2):126. doi:
10.1016/S1472-9792(08)70015-5. Review. PubMed PMID: 18486049.

4: Ginsberg AM. Drugs in development for tuberculosis. Drugs. 2010 Dec
3;70(17):2201-14. doi: 10.2165/11538170-000000000-00000. Review. PubMed PMID:
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Patent ID

Patent Title

Submitted Date

Granted Date

US2016318925 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2016-02-29
US9309238 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2010-11-05
2012-08-30
US7491721 Antimycobacterial pharmaceutical composition
2005-11-17
2009-02-17
US2009118509 PREPARATION OF [2-METHYL-5-PHENYL-3-(PIPERAZIN-1-YLMETHYL)] PYRROLE DERIVATIVES
2009-05-07

///////////////LL 3858, SUDOTERB, TB, LUPIN

CC1=C(C=C(N1NC(=O)C2=CC=NC=C2)C3=CC=CC=C3)CN4CCN(CC4)C5=CC=CC(=C5)C(F)(F)F

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LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865


Sofosbuvir structure.svg

 

(WO2016016865) A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE

LUPIN LIMITED [IN/IN]; 159 CST Road, Kalina, Santacruz (East), State of Maharashtra, Mumbai 400 098 (IN)

ROY, Bhairab, Nath; (IN).
SINGH, Girij, Pal; (IN).
SHRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

The present invention pertains to process for preparing nucleoside phosphoramidates and their intermediates. Phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. One of the recently approved phosphoramidate by USFDA is Sofosbuvir [1190307-88-0]. Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C. The present invention provides novel intermediate, its process for preparation and use for the preparation of Sofosbuvir. The present invention also gives one pot process for preparation of Sofosbuvir.

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. There are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon- [alpha] alone or in combination with the nucleoside analog ribavirin.

US 7964580 (‘580) is directed towards novel nucleoside phosphoramidate prodrug for the treatment of hepatitis C virus infection.

US’580 patent claims Sofosbuvir and rocess for preparation of Sofosbuvir of Formula 1.

Formula 1

Process for preparation of Sofosbuvir as per US ‘580 patent involve reaction of compound of Formula 4″ with a nucleoside 5’

Compound 4″ nucleoside 5′

Wherein X’ is a leaving group, such as CI, Br, I, tosylate, mesylate, trifluoroacetate, trifluroslfonate, pentafluorophenoxide, p-nitro-phenoxide.

Objects of the invention

The object of the present invention is to provide a novel intermediate of Formula 2

Formula 2

wherein X’ is a leaving group selected from 1-hydroxybenzotriazole, 5-(Difluoromethoxy)-lH-benzimidazole-2-thiol, 2-Mercapto-5-methoxybenzimidazole, cyanuric acid, 2-oxazolidinone, 2-Hydroxy Pyridine. The above leaving group can be optionally substituted with n-alkyl, branched alkyl, substituted alkyl; cycloalkyl; halogen; nitro; or aryl, which includes, but not limited to, phenyl or naphthyl, where phenyl or naphthyl are further optionally substituted with at least one of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-C6 haloalkyl, -N(Rr)2, Ci-C6 acylamino, -NHS02Ci-C6 alkyl, -S02N(Rr)2, COR1″, and -S02Ci-C6 alkyl; (Rr is independently hydrogen or alkyl, which includes, but is not limited to, Ci-C2o alkyl, Ci-Cio alkyl, or Ci-C6 alkyl, R1” is -OR1 or -N(Rr)2).

Another object of the present invention is to provide a process to prepare the intermediate of Formula 2.

Another object of the present invention is use of the intermediate of Formula 2 in the preparation of Sofosbuvir of Formula 1.

Formula 1

Example 1:

Process for the preparation of S-oxazolidinone derivative of Formula 2

Step-1 Preparation of phosphorochloridate solution:

Dichloromethane (DCM 400ml) was charged in round bottom flask flushed with nitrogen. Phenyl phosphodichloridate (18.30ml) was added in one portion in the flask. The flask was cooled to -60°-70°C with a dry ice-acetone bath. Solution of L-alanine isopropyl ester hydrochloride (20.6gm)) in DCM (50ml) was added to the reaction flask. To this was added a solution of triethylamine (11.20ml) in MDC (100 ml) was added over a course of 60 minutes, while maintaining internal temperature below -70 °C throughout the addition. After completion of reaction, temperature of reaction mass was raised to room temperature.

100ml THF was charged in another round bottom flask flushed with nitrogen followed by the addition of S-4-phenyloxazolidnone (lOgm). Triethyl-amine (11.2ml) & LiCl (2.85gm) were added to the above flask. The reaction mass was stirred for 15-30 min at room temperature and was cooled to 0-5 °C. Phosphorochloridate solution from step-1 was added drop- wise to the reaction flask in 15-45 min maintaining reaction temperature at 0-5 °C. The reaction mass was stirred for 30-60min at 0°-5°C. The reaction progress was monitored on thin layer chromatography. After completion of the reaction, the reaction temperature was raised to room temperature. Agitation was resumed for an additional 30min. The reaction mass was filtered and concentrated under reduced pressure. To this was added diisopropyl ether (400ml) and aqueous saturated ammonium chloride solution and reaction mass was stirred for 10-15 minutes. Organic layer was separated and was washed with water (100ml) & dried over sodium sulfate and concentrated under vacuum. Cyclohexane (50ml) was charged to the obtained oily mass and reaction mass was stirred till solid precipitated out. Solid was filtered and washed with cyclohexane and dried under vacuum (8.80gm MP 56.5°-56.6°C). The obtained product was characterized by mass, NMR & IR. 1H NMR (DMSO-d6) δ 1.142 -1.18

(m, 9H), 3.85-3.92 (m, 1H), 4.72-4.89(m, 2H), 5.31-5.32(d, 1H), 6.25-6.3 (m, 1H), 6.95-7.31 (m, 10H); MS, m/e 433 (M+l) +

Example 2: Process for the preparation of 2-hydroxy pyridine derivatives of formula 2:

Anhydrous dichloromethane (DCM) 700ml was charged in round bottom flask flushed with nitrogen. The flask was cooled to -60° to -70°C in a dry ice acetone bath. Phenyl phosphodichloridate (76.04 gm) was added in one portion in the flask at -65°C. Solution of L-alanine isopropyl ester hydrochloride (60.56 gm) in DCM (50 ml) was added to the reaction mass. Solution of triethylamine (72.44gm) in DCM (50ml) was added to the reaction mass over a course of 60 minutes, while maintaining internal temperature below -70°C throughout the addition. The resulting white slurry was agitated for additional 60 minutes. Then the temperature of reaction mass was raised to room temperature. Reaction mass was stirred for 60 min & TLC was checked. Reaction mass was filtered and rinsed with anhydrous dichloromethane (2 XI 00 mL). The filtrate was concentrate under vacuum to 20 V and reaction mass was filtered, washed with DCM (15ml). The filtrate was transferred to RBF. The reaction mass was cooled to 0°-10°C. A solution of 2-hydroxy-3-nitro-5- (trifluoromethyl) pyridine (15.gm) in DCM (100ml) & triethyl amine (21.89gm) was added to the reaction mass. Temperature of reaction mass was raised to 20-30°C. Reaction mass was stirred overnight. Reaction was monitored using TLC. After completion, the reaction mass was filtered and washed with DCM (30ml). Filtrate was washed with water (150 ml x 2). Organic layer was concentrated under vacuum and degased. Diisopropyl ether (200ml) was charged to reaction mass and reaction mass was stirred for 15 minutes , filtered and washed with methyl ter-butyl ether (MTBE 30ml). Filtrate was concentrated under vacuum and dried. (8.68gm, MP-125.5°-131.5°C). Obtained compound was characterized by Mass, NMR & IR. 1H NMR (DMSO-d6) δ 1.07 -1.27 (m, 9H), 4.04-4. l l(m, 1H), 4.73-4.79(m, 1H), 6.76-7.43 (m, 5H), 9.00-9.02 (d, 2H); MS, m/e 478 (M+l) +; FTIR, 1203, 1409, 1580, 1732, 3217.

Other 2-hydroxy pyridine derivatives of Formula 2 were prepared by following the process disclosed in example 2-

2-Hydroxy-5-fluoropyridine derivative of Formula 2;-1H NMR (DMSO-d6) δ 1.09 -1.23 (m, 9H), 3.02-3.06 (m, lH), 3.85-4.01 (m,lH), 4.79-4.87(m, 1H), 6.4-6.52 (m,lH), 7.10-7.89 (m,6H); MS, m/e 383 (M+l) +,

2-Hydroxy-5-nitropyridine derivative of Formula 2:- 1H NMR (DMSO-d6) δ 1.06 -1.22 (m, 9H),4.0-4.02 (m,lH), 4.7-4.8(m,lH), 6.5-6.6 (m,lH),7.12-7.42 (m,6H),8.66-8.68 (d, lH),9.07-9.13(d,lH); MS, m/e 410 (M+l) +

2-Hydroxy-3, 5-dinitropyridine derivative of Formula 2:- 1H NMR (DMSO-d6) δ 1.11 -1.24 (m, 9H), 3.04-3.09(m,lH), 4.8-4.86(m,lH), 7.09-7.39 (m,5H),8.97-9.06 (d,2H)

Example 3: Process for the preparation of Sofosbuvir by coupling of isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione :

To a solution of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (0.2gm) in THF (4 ml), tert- butylmagnesium chloride (0.80ml, 1.7 M solution in THF) was added dropwise at room temperature and reaction mass was stirred for 30 minutes. A solution of pyridine derivative from example 2 (0.36gm) in THF (4ml) was added dropwise to the reaction mass at room temperature. Completion of reaction was monitored using TLC. After completion of reaction, reaction mass was quenched by using saturated ammonium chloride solution (10ml). Reaction mass was extracted with ethyl acetate (50ml). Organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel & obtained solid product was characterized. MS, m/e 530.2 (M+l) +.

/////////LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

Lupin Ltd, Patent, Pitavastatin, WO2014203045


Lupin Ltd, Patent, Pitavastatin, WO2014203045

A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE

ROY, Bhairabnath; (IN).
SINGH, Girij, Pal; (IN).
LATHI, Piyush, Suresh; (IN).
AGRAWAL, Manoj, Kunjabihari; (IN).
MITRA, Rangan; (IN).
TRIVEDI, Anurag; (IN).
PISE, Vijay, Sadashiv; (IN).
RUPANWAR, Manoj; (IN)

The present invention describes an eco-friendly and cost effective process for the synthesis of teri-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I]

PITAVASTATIN

TEXT

tert-b tyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I] [CAS No. 124752-23-4] is key intermediate for the preparation of statins such as Atorvastatin (Tetrahedron 63, 2007, 8124 -8134), Cerivastatin (Journal of Labeled Compounds and Radiopharmaceuticals, 49, 2006 311-319), Fluvastatin [WO2007125547; US 4739073], Pitavastatin [WO2007/132482; US2012/22102 Al, WO2010/77062 A2; WO2012/63254 Al ; EP 304063; Tetrahedron Letters, 1993, 34, 513 – 516; Bulletin of the Chemical Society of Japan, 1995, 68, 364 – 372] and Rosuvastatin [WO2007/125547 A2; WO2011/132172 Al ; EP 521471]. Statins are used for treatment of hypercholesterolemia, which reduces the LDL cholesterol levels by inhibiting activity of HMG-CoA reductase enzyme, which is involved in the synthesis of cholesterol in liver.

[I]

Compound [I] is generally obtained by various methods of oxidation of teri-butyl 2- ((4R,65)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate [compound II] and are discussed in details hereinafter. In addition, various methods for synthesis of compound [II] are also elaborated below.

[II]

[II]

A) tert-butyl2-((4«,6.S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate

[compound II]

US patent Number 5278313 describes a process for synthesis of compound [II]

(Schemel). In the said process, (5)-methyl 4-chloro-3-hydroxybutanoate has been obtained in only 70% yield through whole cell enzymatic reduction of methyl 4-chloro-3- oxobutanoate, which has a necessity of special equipment such as fermenters as well as other microbial facilities such as sterile area, autoclaves, incubator for growing seed culture, etc.

(S)-mefhyl 4-chloro-3-hydroxybutanoate upon reaction with teri-butyl acetate in presence of LiHMDS or LDA at -78°C, yielded (S)-ieri-butyl 6-chloro-5-hydroxy-3- oxohexanoate, which was further transformed to corresponding diol through syn selective reduction in presence of methoxydiethyl borane/sodium borohydride at -78°C. The diol thus obtained was converted to compound [II] .

The overall yield for this process is low and required special equipment such as fermenters, etc and in addition to that, this process is not cost effective due to use of costly reagent such as methoxydiethyl borane.

Moreover, methoxydiethylborane is highly pyrophoric (Encyclopedia for organic synthesis, editor in chief L. Paquette; 2, 5304; Published by John and Wiley Sons;

Organic Process Research & Development 2006, 10, 1292-1295) and hence safety is a major concern.

Scheme 1

EP 1282719 B l (PCT application WO 01/85975 Al ) discloses a process for synthesis of compound ( R, 5S)-tert-bv y\ 3,5,6-trihydroxyhexanoate from (S)-tert-b tyl-5,6-dihydroxy-3-oxohexanoate through a) asymmetric hydrogenation in presence of a chiral catalyst e.g. di-mu-chlorobis-[(p-cymene)chlororuthenium(II)] along with an auxiliary such as (IS, 2S)-(+)-N- (4-toluenesulfonyl)-l ,2-diphenylethylenediamine as ligand, which gave desired product only in 70% diastereomeric excess (de); b) Whole cell enzymatic reduction of (S)-tert- butyl 5,6-dihydroxy-3-oxohexanoate to obtain compound (3R, 5S)-tert-bv y\ 3,5,6-trihydroxyhexanoate in 99% de (80% yield).

It is needless to mention that it has necessity of fermenter and other microbiological equipment (Scheme 2).

Moreover, conversion of (2>R,5S)-tert-bv y\ 6-acetoxy-3,5-dihydroxyhexanoate to tert-bv yl 2-((4R,65)-6-(acetoxymethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate was accomplished in only 25% yield and also required the flash chromatography for isolation of desired product.

Thus, overall yield for this process is poor and process is not operation friendly especially at large scale hence cannot be considered feasible for commercial manufacturing.

Scheme 2

EP1317440 Bl (PCT Application WO 02/06266 Al) has disclosed the process for synthesis of compound [II] from 6-chloro-2,4,6-trideoxy-D-erythro-hexose (Scheme 3) .

In the said patent application 6-chloro-2,4,6-trideoxy-D-erythro-hexose was converted to (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2one with excess of bromine in presence of potassium bicarbonate, which liberates environmentally undesired gas i.e. carbon dioxide.

Moreover, starting material i.e. 6-chloro-2,4,6-trideoxy-D-erythro-hexose is not commercially available and conversion efficiency of starting material at large scale towards (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2-one is only 67%.

Scheme 3

US Patent No. 6689591 B2 has demonstrated the whole cell enzymatic reduction of teri-butyl 6-chloro-3,5-dioxohexanoate to compound [II] (Scheme 4).

In the said process, whole cell enzymatic reduction is not specific; yield for desired product is only 34% and other partially reduced products are also obtained.

Hence, further purification is required for obtaining the desired compound. Thus, this process is not suitable for commercial scale.

Scheme 4

Tatsuya et al (Tetrahedron Letters; 34, 1993,513 – 516) has reported synthesis of compound [I] from derivative of L-tartatric acid (Scheme 5).

In the said process, tartaric acid di-isopropyl ester is doubly protected by tert-butyldimethylsilyl group, which was reacted with dianion of teri-butyl acetoacetate to give β, δ-diketo ester compound.

β,δ-diketo ester was reacted with 2 equivalent of diisobutylaluminium hydride (which is a pyrophoric reagent) to afford -hydroxy,8-keto ester in only 60% yield.

This process is not industrially viable as overall yield is very low and also because of use of costly and pyrophoric reagents/chemicals.

Scheme 5

US7205418 (PCT application WO03/053950A1) has described the process for synthesis of compound [II] from (S)-ieri-butyl-3,4-epoxybutanoate (Scheme 6).

The overall yield for this process is very low and moreover, it required the diastereomeric separation of teri-butyl 2-(6-(iodomethyl)-2-oxo-l,3-dioxan-4-yl)acetate by flash chromatography.

Since overall requirement of title compound is very high, any operation involving flash chromatography will tend to render the process commercially unviable.

Scheme 6

Fengali et al (Tetrahedron: Asymmetry 17; 2006; 2907-2913) has reported the process for synthesis of compound [II] from racemic epichlorohydrin (Scheme 7).

In this process, racemic epichlorohydrin was converted to corresponding nitrile intermediate through reaction with sodium cyanide; nitrile intermediate thus obtained was further resolved through lipase catalyzed stereo-selective esterification to obtain (5)-4-(benzyloxy)-3-hydroxybutanenitrile and (R)-l-(benzyloxy)-3-cyanopropan-2-yl acetate;

separation of desired product i.e. (S)-4-(benzyloxy)-3-hydroxybutanenitrile having 98% de (40% yield) was done by column chromatography.

Needless to mention a commodity chemical like compound [I] cannot be manufactured by such a laboratory method, which involved number of steps.

Scheme 7

Bode et al (Organic letters, 2002, 4, 619-621) has reported diastereomer- specific hydrolysis of 1,3-diol-acetonides (Scheme 8).

In this publication, duration of the reaction for diastereomer- specific hydrolysis of 1,3, diol-acetonides is reported to be 4 h, however, in our hand it was observed that hardly any reaction took place in 4 h, which made it non-reproducible.

In addition to that, separation of desired product is achieved by flash chromatography and it is needless to mention that any process which involved flash chromatography would render the process to be commercially unviable.

Hence, additional innovation needs to be put in for making the process industrially viable.

Scheme 8

CN 101613341A has reported the process for synthesis of compound [II] (Scheme

9).

In the same patent application tert-b tyl (S)-6-chloro-5-hydroxy-3-oxohexanoate was synthesized through Blaise condensation of (5)-4-chloro-3-hydorxy-butanenitrile with zinc enolate of tert butyl bromo acetate.

In the literature, synthesis of tert-bv yl (S)-6-chloro-5-hydroxy-3-oxohexanoate was reported through Blaise condensation of silyl protected (5)-4-chloro-3-(trimethylsilyl)oxy-butanenitrile with zinc enolate of tert butyl bromo acetate, in good yield (Synthesis 2004, 16, 2629-2632). Thus, protection of hydroxy group in (5)-4-chloro-3-hydorxy-butanenitrile is imperative.

In the said Chinese patent application, in claim 7, it was mentioned that solvent used for conversion of tert-bv yl (5)-6-chloro-5-hydroxy-3-oxohexanoate to ( R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate is anyone or mixture of more than one from tetrahydrofuran, ether, methanol, ethanol, n-propanol, /so-propanol and ethylene glycol.

However, in enablement the only example using mixture of solvent was that of THF-methanol (Experimental section, Example 4: The preparation of (R,5)-6-chloro-3,5- dihydroxyhexanoate) and same outcome was expected in other individual or mixture of solvents.

Claim 8 of CN 101613341A mentioned that reduction was carried out by any one or mixture of more than one reducing agents such as sodium borohydride, potassium borohydride, lithium aluminum hydride, diethylmethoxy borane, triethyl borane and tributyl borane.

It implies that either any one of the reducing agents or a mixture of the same can be employed. From reaction mechanism it is very much clear that diethylmethoxy borane, triethyl borane and tributyl borane form the six membered complex between optically active hydroxyl and carbonyl group, which gets reduced by sodium borohydride, signifying that individually diethylmethoxy borane, triethyl borane and tributyl borane are not reducing agents

Moreover, in claims 12 and 13 (Experimental section, Example 4: The preparation of (R,S)-6-chloro-3,5-dihydroxyhexanoate), it is mentioned that reduction should be carried out in temperature range -80 °C to -60 °C, implying that reaction would not work beyond this temperature range i.e. it would work in the temperature window of -80 °C to -60 °C only.

Summarizing, the teachings of the application are not workable.

Scheme 9

Wolberg et al (Angewandte Chemie International Edition, 2000, 4306) has reported that diastereomeric excess for syn selective reduction using mixture of diethyl methoxy borane/sodium borohydride of compound [VI] gave 93% de for compound [VIII], which required further re-crystallization to obtain compound [VIII] in 99% de and 70% yield.

Thus, all the reported methods for stereo-selective hydride reduction of compound [VI] were achieved through mixture of trialkyl borane or diethyl methoxy borane & sodium borohydride in THF, at -78°C. As mentioned earlier, trialkyl borane or diethyl methoxy borane are pyrophoric in nature; in addition to that anhydrous THF is costly and moreover, reaction required large dilution.

Hence, there is need for developing efficient, environment friendly, cost effective and green process for stereo-selective reduction compound [VI].

B) The process of Oxidation of compound [II] to compound [I] has been discussed in following literature processes.

1) Swern oxidation (US4970313; Tetrahedron Letters, 1990, 2545

Synthetic Communications, 2003, 2275 – 2284).

2) Parrkh-Doering oxidation (J. Am. Chem. Soc, 1967, 89, 5505-5507)

3) TEMPO/NaOCl oxidization (EP2351762)

4) Trichloroisocyanuric acid/ TEMPO (CN 101747313A)

5) Oxidation of compound [II] to compound [I] through IBX [CN101475558A].

It would be evident that most of the reported methods are not “green” and

environmentally benign; none of the reported methods use molecular oxygen as oxidizing agent in presence of metal catalyst/co-catalyst.

Example 18: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate [I]

A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of acetonitrile. 2-2′ Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

Example 19: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate [I]

A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of dichlorome thane. 2-2′ Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

AUTHORS

SEE………https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014203045&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCT+Biblio

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Lupin buys Brazilian pharmaceutical firm Medquímica


 

Lupin buys Brazilian pharmaceutical firm Medquímica
India-based drugmaker Lupin has acquired 100% equity interest in Brazilian pharmaceutical firm Medquímica Indústria Farmacêutica.

read at

http://www.pharmaceutical-technology.com/news/newslupin-buys-brazilian-pharmaceutical-firm-medqumica-4578219?WT.mc_id=DN_News

Group president and CEO, Lupin Pharmaceuticals, and director on the board of Lupin Limited, Vinita Gupta

Medquímica

.

A Medquímica Indústria Farmacêutica é uma empresa genuinamente brasileira que atua na produção de medicamentos para o uso humano. Com sua linha de produção instalada em Juiz de Fora, a Medquimica está presente em todo o Brasil através de seus representantes.

Working in syntony with the market. There are 30 years that it is the north that takes the Medquímica Pharmaceutical Industry Ltda. to dedicate to the production of pharmaceutical products of proven effectiveness and certain return for all its net of customers. For such, the Medquímica invests in physical and human resources, forming a qualified and highly experienced technical team, who detaches in the marketplace for producing medicines of uncontestable quality and trustworthiness.

With the quality certified through the Good Practical of Manufacture, the Medquímica detaches for having a laboratory of reference inside its installations. Moreover, respecting the resolution 134 from Anvisa, gradually, all its medicines are being evaluated for the tests of pharmaceutical equivalence, proving, in this way, the quality of Medquímica’s product. Such actions had resulted in a supported growth of credibility and sales.

For giving support to all this development, the Medquímica will start the construction of the first projected national plant in the most rigorous and recent requirements of the ANVISA. Thirty years of history, qualified technician team, tests of equivalence and bioequivalência and a model plant makes from Medquímica the certain alternative for the success of its businesses

Fábrica:
(32) 3224-4087 (Telefax)

Administração:
(32) 2101-4000 (Telefax)

The Medquímica Pharmaceutical Industry is a genuinely Brazilian company that acts in the medicine production for the human use. With its line of production installed in Juiz de Fora, the Medquimica is present in all over Brazil through its representatives.

Industry
Rua Otacílio Esteves da Silva, 40
Bairro Granjas Betânia
CEP: 36047-400
Juiz de Fora – MG

Administration
Rua Fernando Lamarca, 255
Bairro Distrito Industrial
CEP: 36092-030
Juiz de Fora – MG

Juiz de Fora

Map of juiz de fora

Paço Municipal de Juiz de Fora

 

No todo parece bem interessante. Dá pra tirar muitas fotos boas. Já teve outro thread bem legal sobre a cidade.

 

 

 

 

 

Lupin and Celon Pharma partner for generic version of GSK’s Advair Diskus


 

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin

India-based drugmaker Lupin has signed an agreement with Polish biopharmaceutical firm Celon Pharma to develop a fluticasone / salmeterol dry powder inhaler (DPI).

Under the deal, Lupin will take the responsibility for commercialisation of the product, which is a generic version of GlaxoSmithKline’s (GSK) Advair Diskus.

Lupin CEO Vinita Gupta said: “We are very pleased to partner with Celon given their experience in the development and manufacturing of fluticasone/salmeterol DPI in Europe…………..http://www.pharmaceutical-technology.com/news/newslupin-celon-pharma-partner-generic-version-gsks-advair-diskus-4514718?WT.mc_id=DN_News

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin, is based in the United States, but has been in India a lot in the past one year.

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin,
Vinita Gupta

With an expanding role in Lupin’s universe, Vinita has been spending more time outside the US, at times taking her six-year-old son, Krish with her. “He is getting exposure at a much younger age,” she says. Gupta herself was exposed to business at the age of 11 by her father Desh Bandhu Gupta, Lupin’s founder and Chairman.

“We almost had a family board at home, discussing work,” she says. Currently work goes well indeed, with Gupta taking new initiatives in India and also making the business more global. “I am focusing on drivers for growth in our business for the next five years,” she says.

Gupta is married to US-based businessman Brij Sharma.

 

 

 

 

DB Gupta (centre) Chairman, Vinita Gupta (right) CEO and Nilesh Gupta

 

Lupin launches insulin glargine in India


lupin ltd biosimilarnews Lupin launches insulin glargine in India

Lupin launches insulin glargine in India:

Indian pharma company, Lupin Limited announced a strategic distribution agreement with LG Life Sciences of South Korea to launch Insulin Glargine, a novel insulin analogue under the brand name Basugine™.

According to the agreement, Lupin would be responsible for marketing and sales of Basugine™ in India.

READ MORE

http://www.biosimilarnews.com/lupin-launches-insulin-glargine-in-india?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

Lupin forms joint venture with Yoshindo


 

Lupin forms joint venture with Yoshindo
Indian pharmaceutical company Lupin is to create a new biosimilars company in a joint venture with Japanese pharmaceuticals company Yoshindo. The new company, to be called YL Biologics (YLB), will be jointly managed by both partners and will develop biosimilars including regulatory filings and…

read at

http://www.manufacturingchemist.com/news/article_page/Lupin_forms_joint_venture_with_Yoshindo/97981/cn48579?dm_i=8EU,2FAE5,9ETTTY,8T8OK,1

 

LUPIN.. giant leap forward » All About Drugs


LUPIN.. giant leap forward » All About Drugs

Merck and Lupin collaborate to co-market Merck’s Pneumovax 23 Pneumococcal polysacharide vaccine for Indian market


Merck has partnered with India based Lupin to co-market its pnemococcal vaccine in India. Lupin gets a non-exclusive license to market, promote and distribute Pneumovax under a different brand name in India. With patients suffering from respiratory disease like Asthma as candidates for pneumococcal vaccination,  Lupin which has a strong presence in this segment seems to be a right choice.
 The Pneumococcal vaccine is sold under the brand name Pneumovax 23 in the US…………….
read all at

Pneumococcal polysaccharide vaccine (PPSV) — the latest version is known asPneumovax 23 (PPV-23) — is the first pneumococcal vaccine, the first vaccine derived from a capsular polysaccharide, and an important landmark in medical history. The polysaccharide antigens were used to induce type-specific antibodies that enhanced opsonization, phagocytosis, and killing of pneumococci by phagocytic cells. The pneumococcal polysaccharide vaccine is widely used in high-risk adults. As a result, there have been important reductions in the incidence, morbidity, and mortality from pneumococcal pneumoniae and invasive pneumococcal disease.

First used in 1945, the tetravalent vaccine was not widely distributed, since its deployment coincided with the discovery of penicillin. In the 1970s, Robert Austrian championed the manufacture and distribution of a 14-valent PPSV. This evolved in 1983 to a 23-valent formulation (PPSV23). A significant breakthrough impacting the burden of pneumococcal disease was the licensing of a protein conjugate heptavalent vaccine (PCV7) beginning in February 2000.

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